Antiretroviral (ARV) drugs are medications for the treatment of infection by retroviruses, primarily human immunodeficiency virus (HIV). The American national institutes of health and other organizations recommend offering antiretroviral treatment to all patients with acquired immune deficiency syndrome (AIDS).
Among the antiretroviral drugs which have been developed are those which target the HIV reverse transcriptase (RT) enzyme or protease enzyme, both of which enzymes are necessary for the replication of the virus. Examples of RT inhibitors include nucleoside/nucleotide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). Currently, HIV-infected patients are routinely being treated with three-drug combinations. Regimens containing (at least) three NRTIs; two NRTIs in combination with one or two protease inhibitors (PI)(s); or two NRTIs in combination with a NNRTI, are widely used.
Clinical studies have shown that three-drug combinations of these anti-HIV drugs are much more effective than one drug used alone or two-drug combinations in preventing disease progression and death. Numerous studies of drug combinations with various combinations of such drugs have established that such combinations greatly reduce disease progression and deaths in people with HIV infections. The name now commonly given to combinations of anti-HIV drugs is HAART (Highly Active Anti-Retroviral Therapy).
A variety of antiretroviral drugs approved by the United States Food and Drug Administration (USFDA) and were commercially available in various dosage forms and strengths; for example Lamivudine, Stavudine, Zidovudine, Ritonavir, Saquinavir, Abacavir, Entecavir, Darunavir, Nevirapine, Efavirenz, Tenofovir disoproxil, Emtricitabine, Atazanavir and Raltegravir etc.
Antiretroviral drugs in pharmaceutical compositions can be prepared in a variety of different forms. Such drugs can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts. Such drugs can also be prepared to have different physical forms. For example, the drugs may be amorphous or may have different crystalline polymorphs, perhaps existing in different solvates or hydrate states. By varying the form of a drug, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, color, and compressibility.
PCT publication WO 99/05150 discloses tenofovir disoproxil fumarate characterized by powder X-ray diffraction (PXRD) and differential scanning calorimeter (DSC).
PCT publication WO 2009/074351 discloses solid forms of tenofovir disoproxil acid addition salts selected from the group consisting of succinic acid, tartaric acid, saccharic acid, citric acid, oxalic acid and salicylic acid. The '351 publication discloses characterization of the solid forms by PXRD peaks.
CN Publication No. 101712692 discloses tenofovir disoproxil acid addition salts including hydrochloric acid, sulfuric acid, phosphoric acid, toluene sulfonic acid, salicylic acid, benzoic acid, formic acid, citric acid, fumaric acid, maleic acid, malic acid.
U.S. Pat. No. 6,329,522 discloses Lamivudine and its acid addition salt such as salicylic acid and process for the preparation of the same.
PCT publication WO 2010/082128 discloses Lamivudine succinic acid and Lamivudine dicinnamic acid and process for the preparation of the same.
U.S. Pat. No. 6,294,540 discloses abacavir acid addition salts selected from sulfate, glutarate, benzoate, salicylate and dicarboxylate salts (glutarate, hemisuberate, adipate, fumarate, sebacate and pimelate). PCT publication WO 96/06844 discloses abacavir succinic acid salt.
U.S. Pat. No. 6,600,044 discloses emtricitabine acid addition salts such as methane sulfonic acid and hydrochloric acid.
It would be advantageous to have new forms of antiretroviral drugs that have improved properties, in particular, as oral formulations. Specifically, it is desirable to identify improved forms of the drug that exhibit significantly increased aqueous solubilities and stability. It is also desirable to increase the dissolution rate of drug-containing pharmaceutical compositions in water, increase the bioavailability of orally-administered compositions, and provide a more rapid onset to therapeutic effect. It is also desirable to have a form of the drug which, when administered to a subject, reaches a peak plasma level faster and/or has a longer lasting plasma concentration and higher overall exposure at high doses when compared to equivalent amounts of the drug in its presently-known form.